MARCH,1963
SUBSTITUI'ION d T T H E CARBON-LEAD
drolysis to the acid using sodium hydroxide solution, and isolation of the corresponding benzylthiouronium derivative. Recrystallization from aqueous alcohol gave pure CH3(CF,)C=CFCOO-I-
NHZ=C( O H ~ ) S C H & O H181-183 ~, Of Anal. Calcd. for ClaHl4F4NzO~S: C, 46.15; H, 4.14. Found: C, 45.85; H, 4.20.
BOND
843
Acknowledgment.-The authors gratefully acknowledge the financial support of this research by the Quartermaster Research and Engineering Command, U. S. Army, Natick, hlassachusetts, with Dr. J. C. Montermoso and Mr. C. B. Griffis as the project officers.
Electrophilic Substitution at the Carbon-Lead Bond G. C. ROBINSON Ethyl Corporation, Baton Rouge, Louisiana Received July 27, 1962 The rates of acetolysis of tetramethyllead, tetraethyllead, tetra-n-propyllead, tetra-n-butyllead, and tetraisoamyllead were determined a t 24.9, 49.8, and 60.0'. A reactivity series methyl > ethyl > n-propyl s n-butyl isoamyl was found. The entropies and enthalpies of activation were very similar for all these compounds. The rate of acetolysis of tetra-n-butyllead was, surprisingly, almost identical with that of di-n-butylmercury. Perchloric acid cleavage in acetic acid solvent gave a reactivity series similar to that in acetolysis.
Few quantitative data on rates of electrophilic substitution a t saturated carbon atoms are available. Data on cleavage by protonic acids of a metal-alkyl bond are particularly limited. We report here the rates of acetolysis a t three temperatures of a series of tetra-n-alkyllead compounds. R4Pb
+ 110.4~+RH + RsPbOAc
Thc rate of cleavage of these same compounds by perchloric acid in acetic acid solvent was also determined. RaPb
+ HCIO, +R H + RsPbC104
The only directly comparable data in the literature mere obtained by Winstein and Traylor' on organomercury compounds. Dessy and his co-workers2 have also studied rates of hydrogen chloride cleavage of organomercury compounds. This latter work was largely in mixed solvents, and the data obtained are not directly comparable to those in this paper. Results Table I summarizes the acetolysis data obtained during this work, together with the derived entropies and enthalpies of activation. Table I1 shows detailed data for a typical acetolysis run. In Table I11 are collected the data on rates of perchloric acid cleavage in acetic acid solvent. A typical perchloric acid cleavage run is presented in detail in Table IV. The required control experiments are described in the Experimental. Discussion We have used the kinetic data to calculate relative reactivities in electrophilic substitution a t the primary carbon atoms in this series. The results are summarized in Table V. For these relative reactivities to be meaningful it must be shown that special steric effects due to the quaternary lead atom are not affecting the rate constants. It must be assumed also that the change in trialkyllead cation formed on cleavage as one proceeds through the series of tetraalkyllead compounds (1) (a) S. Winstein and
T. G . Traylor. J . A m . Chem. hoc., 77, 3747 (1955);
(b) 7 8 , 2597 (19.56). ( 2 ) (a) It. 1L DrYsy and J. Y. K i m . zbid., 83, 1167 (1961); (b) R. E. l)cssy, G. 1'. Ilcynolds, a n d J. Y. Kim, i b i d . , 81, 2683 9(159).
does not substantially alter the reactivity of the leadalkyl bonds. Inspection of the enthalpies and entropies of activation in Table I makes it clear that no large steric effects are present, for the enthalpies and entropies of activation are all very similar. Such steric effects would not be expected a priori since a lead atom has twice the radius of a carbon atom. It is unlikely that variable inductive stabilization of the iiicipient trialkyllead cations affects our reactivity sequence; the large size of the lead atom should attenuate to insignificance this secondary inductive effect. Support for this view is obtained from recent work in silicon chemistry. Russel and Napgal have studied the rates of cleavage of alkyltrimethylsilanes with hydrogen bromide and aluminum b r ~ m i d e . ~They find a reactivity sequence CHs >> C2Hb (1.0) > YL-C~H? (0.13) n-CdH9(0.17) with a constant trimethylsilyl leaving group. This reactivity series is similar to those reported in Table T' and indicates that the reactivity order may be general in electrophilic substitution. A similar qualitative order was found by Whitmore and Bernstein4for the cleavage of alkyl groups from organomercury compounds. The relative rate data from acetolysis at 25, 50, and 60" are self-consistent within the limits of error. The perchloric acid cleavage data show the same reactivity order as acetolysis but with a wider spread between methyl and ethyl. These reactivity orders are not those one would predict for simple inductive effects on S E ~reaction^.^ I n fact, the relative rates resemble those observed in 8x2 reactions.6 A point of similarity between S Nand ~ S E reactions ~ is the presence of five-coordinate carbon in the transition state in each. The similar reactivities in S s 2 and S E reactions ~ may arise from some such general feature of the transition states. Russel and Sapga13 consider that their relative rates of alkyltrimethylsilane cleavage are due to an undefined steric effect. This suggestion seems reasonable but we have no really specific a i d ( 3 ) G. A . Russel and K. L. Napgal, Tetrahedron Letters, 421 (1961). (4) F. C. Wliitmore and H. Bernstein, J . A m . Chem. Soc., 60, 2626 (193b). (5) E. n. Hughes and C. K. Ingold, J . Chem. Sor., 244 (1935). (6) L. P. Harnmett. "Physical Organic Chemistry," AIcGraw-llill Book
Co., Inc., New York, N. Y.,1940, p.
154.
VOL.28
ROBINSOS
844
TABLE I RATESOF ACETOLYSIS OF TETRAALKYLLEAD COMPOUKDS _._I__ Compound
kl X 105,sec.-l--
24.9'
(CHa)4Pb
AH*.
49.8'
1.16 f 0 . 0 3
(CzHrIrPb
kcal./mole
60.0°
16.4f0.2 17.9 f 1 . 3 11.3f0.6 1 0 . 5 4 ~.7 3 . 1 f . 2 4 . 3 f .1
0.92 f .06" .67 f .08" ( CHaCH*CHz),Pb ,225f.013 [CHI(CHP)IIrPb . 3 1 1 f ,005 .2G f , 0 2 6 [(CHa)2CHCH2CHz)]4Pb . 3 0 0 f ,015 4 . 2 f .3 a A t 26.0". Rate from determination of unchanged
41.2f1.3
20.8
28.7f1.8 2 7 . 7 3 ~l . l b 8.2f0.4 1 0 . 6 f .4
20.7 21.2
-15 -13
1 2 . 2 f .5 21.2 tetraethyllead.
-13
(CHaM'b (CzH6)J'b (CHaCH&H2)4Pb [CHdCHz)aIcPb [( CHa)&HCHzCHa]4Pb
0.0110 ,0092 ,0118 ,0134 .0133
0.0104 ,0104 .0259 ,0134 ,0104
kn, l./mole-sec.
0.22 f O . O 1 ,024 f ,002 ,0089 f ,0003 . 0 0 6 8 f ,0002 .0059 f ,0001
TABLE V RELATIVE CLEAVAGE RATES r,
Acid
lenip., 'C.
CHs
CzHr
n-CsH7
n-CkHs
i-CsH11
HOAc HOAc HOAc HClOc
24.9 49.8 60.0 25.0
1.0 1.0 1.0 1.0
0.79 ,65 .68
0.19 .18 .20
0.27
.ll
.04
0.26 .25 .30 .03
.25
.26 .03
verifiable hypothesis to present a t present as an explanation of these unexpected relative reactivities. The data of Winstein and Traylor' permit a direct comparison of their data on the acetolysis of dibutylmercury with our data on acetolysis of tetrabutyllead. These data are summarized in Table VI. The similarities are striking. It is likely that these similarities between lead and mercury alkyls are general in the normal alkyl series. Comparative data on thallium and bismuth alkyls would be of interest since bismuth and thallium are adjacent to lead and mercury in the periodic table. If the rates of cleavage of these metal alkyls are similar to those of lead and mercury, it will demonstrate that a t high atomic numbers bond characteristics are little affected by bond type.
Experimental Materials.-A single supply of acetic acid was used. Its water content was determined as 0.2 wt. % by Karl Fischer titration. Tetramethyllead, tetraethyllead, tetra-n-butyllead, and tetraisoamyllead were supplied by the Ethyl Corp. Tetran-propyllead was prepared by the procedure of Griittner and Krause.' A standard 0.0100 ,If solution of sodium acetate in acetic acid was prepared from sodium carbonate and glacial acetic acid. Approximately 0.01 ,If and 0.05 M solutions of perchloric acid in glacial acetic acid were prepared from 707;) aqueous perchloric acid. The 0.05 J I solution was dried with acetic anhydride. These solutions were standardized against the sodium acetate solution using a saturated solution of txonivcresol green (Sational Aniline) as indicator.
kl x 105,
Titer, ml.
880. -1
0.06 ... .80 1.19 1.46 1.15 2.17 1.11 3.05 1.14 4.20 1.16 5.12 1.23 6.36" Mean K 6 f 0.03 a Seven half-lives, 97% of calculated titer. 0 3 6 10 15.2 24.4 34 120
TABLE IV CLEAVAGE OF TETRAETHYLLEAD BY PERCHLORIC ACID (25.0' in HOAc solvent) Time, sec.
Initial concentration, ---moles/l.-R4Pb HClO4
Time, hr.
-12 -15
COMPOUNDS (25.0" in HOAc solvent)
(24. go, calcd. titer 6.56 ml.)
AS*, e.u.
20.1
TABLE I11 RATESOF PERCHLORIC ACID CLEAVAGE OF TETRAALKYLLEAD
Compound
TABLE:II
RATE OF :ACETOLYSISLOFTETRAMETHYLLEAD
Concn., m o l e s / l . - F HClO4 (CzHdrPb
kZ1 1.,'niole-sec.
... 0 0.0104 0.0092 0.037 ,0098 180 ,0086 ,028 ,0091 ,0079 600 ,024 ,0071 1200 .0083 ,021 2100 .0062 .0074 ,023 ,0053 3000 ,0065 ,022 4200 ,0058 ,0046 __. Mean 0 024 f 0.002" a Yalue a t 180 sec. omitted. TABLE VI COMPARISON O F TETR.4-n-B CTYLLEAD WITH IX ACETOLYSIS
1)I-7L-BUTYLMERCLRY'
(50') Compound
(n-CcHo)J'b (n-CaH9)zHg a Data from ref. 1.
105kl, sec. -1
AH*.
AS *
kcal./mole
cal./mole OC.
4.3 3.8
21.2 20.4
- 13 - 16
Rates of Acetolysis.-Rates of acetolysis were followed by a sealed ampoule technique.1" The rate of formation of trialkyllead acetate was followed by titration with 0.01 M perchloric acid in acetic acid. Reaction solutions were ca. 0.01 M t o minimize acid cleavage during titration. This low concentration also minimized disproportionation of trialkyllead acetate to tetraalkyllead and dialkyllead diacetate. First-order rate constants were computed using a calculated initial concentration. Experimental infinities were within 5% of the calculated infinities. No systematic trends were noted in any of the rate constants. Reactions were followed to 80% completion or more. It was shown that, a t 60.0°, 0.01 M solutions of trimethyllead acetate and triethyllead acetate did not observably change in titer during 32 half-lives of the parent lead alkyls. A similar stability was assumed for the other trialkyllead acetates. A check on the analytical procedure used for following the rate of acetolysis was devised. It involved determination of unchanged tetraalkyllead rather than titration of the acetate ion formed. This method was applied to acetolysis of tetraethyllead a t 60.0". The individual samples (10 ml.) were prepared for analysis of unchanged tetraethyllead by partition between 10 ml. of benzene and 25 ml. of water containing 10 g. of sodium hydroxide. The aqueous layer was separated and extracted with 5 ml. more benzene. The benzene extracts were combined and analyzed for tetraethyllead by iodometric titration.* The rate constant obtained agreed well with that derived using titration of acetate ion. Rates of Perchloric Acid Cleavage.-The perchloric acid solution used in this study was 0.0519 M . The reaction mixtures wcrc prepared by wcighing out the tetraalkyllcad compound to ( 7 ) 0.Grhttner and E. Krause, Ber., 60, 278 (1917). ( 8 ) Fr. Hein, A. Klein, a n d H. J. l\les&e,2. anal. Chem.. 116, 177 1193LI).
hfARCH,
THIOSUGARS. I1
1963
the nearest 0.1 mg. and adding the requisite amount of acetic acid a t 28.0" with an automatic pipet. Then the desired amount of perchloric acid solution was added to the magnetically stirred solution of lead alkyl, using the same automatic pipet. The reaction mixture was immediately immersed in a constant temperature bath a t 28.0'. Aliquot samples were removed periodirally and titrated for acid content using a 0.0100 M solution of
Thiosugars.
s45
sodium acetate in acetic acid. The reactions were followed to at least 50% completion. Rate constants were calculated using an integrated form of the second-order rate equation, assuming the reaction t o be first order in perchloric acid and first order in tetraalkyllead compound. The form assumed for this reaction was verified by the constancy and freedom from drift of the rate constants obtained.
11. Rearrangement of 2-(3,4,6-Tri-0-acetyl-2-amino-2-deoxy~-~-glucopyranosyl)-2-thiopseudourea~~~~ M. L. WOLFROM, D. HORTON, AA-D D. H. HGTSOX* Department of Chemistry, The Ohio State University, Columbus 10, Ohio Received October 25, 1962
In neutral solution 2-(3,4,6-tri-0-acetyl-?-amino-2-deoxy-~-~-glucopyranosyl)-2-th~opseudourea dihydrobromide ( I ) undergoes rearrangement to form 3,4,G-tri-O-acetyl-2-deoxy-2-guanidino-l-thio-~-glucose (111). A product from the acetylation of I in acidic solution 1% as identical with 1,3-di-N-acetyl-2-(2-acetamido-3,4,6-tri-O-acetyl2-deoxy-~-~-glucopyranosyl)-2-thiopseudourea (11) which had been prepared by acetylation of 2-( 2-acetamido3,4,6-tri-0-acetyl-2-deoxy-~-~-glucopyranosyl)-2-thiopseudourea hydrochloride (IV). The behavior of I and related derivatives on desulfurization is discussed.
The condensation of 3,4,6-tri-O-acetyl-2-amino-2desulfurization. la The present work establishes a dideoxy-a-D-glucopyranosyl bromide hydrobromide with rect correlation between I and IV by acetylation to the thiourea was described in part I,Iaand the product was same derivative, and firmly establishes the existence of formulated as 2-(3,4,6-tri-O-acetyl-2-amino-2-deoxy-fl-a C-1 to S bond in I. Acetylation of IV in pyridine ~-g~ucopyranosyl)-2-thiop~udourea dihydrobromide with acetic anhydride gave a crystalline product, con(I) by analogy with the products formed by condensataining two more acetyl groups, formulated as 1,3-di-Ntion of other glycosyl halide derivatives with thiourea. acetyl - 2 - ( 2 - acetamido - 3,4,6- tri - 0 - acetyl - 2Optical rotatory data supported a 0-D anomeric condeoxy - fl - D - glucopyranosyl) - 2 - thiopseudourea (11). figuration. I n the case of the N-acetyl hydrochloride The possibility of anomerization in this reaction is very analog of I, 2-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy- improbable. Under the same conditions, acetylation fl-~-g~ucopyranosyl)-2-thiopseudourea hydrochloride of I gave no trace of 11, although the thin layer chro(IV), the C-1 t o S linkage was established by reductive matographic procedure used would have revealed this product in very low concentration in the reaction mixTH20Ac f;" CHzOAc YAc ture. This is to be expected in view of the readiness with which I rearranges in neutral or basic media, as described below. Acetylation with acidic catalysts permits reversible anomerization, and the thermodynamically more stable anomer preponderates in the product a t equilibrium. Acetylation of either I or IV with acetic anhydride and zinc chloride under the same conditions gave a mixture of two principal products in each case, with identical Rf values and intensities on thin layer chromatograms. The product formed in CH~OAC Q-C-NH~.HCI CH20Ac lesser amount was isolated from each reaction mixture and was shown to be identical with 11; the other product was probably the a-Danomer of 11. AcOQH AcO Compound I was synthesized as a carbohydrate anaNH--C-NH,.HX NHAc log of 2-(2-aminoethyl)-2-thiopseudourea (AET) hyI/ drobromide, which is one of the best known agents for KH IV protection of mammals against ionizing r a d i a t i o i ~ ~It I11 was hoped that a carbohydrate analog might retain this protective ability while exhibiting reduced toxicity. It bas been shown6that the protective ability of 2-(2aminoethyl)-2-thiopseudourea is retained in the propyl analog 2-(3-aminopropyl)-2-thiopseudourea(APT) hydrobromide, but that activity falls off rapidly as the length of the alkyl chain is extended further. The protective activity of these two thiopseudourea derivatives
$;""
( I ) ( a ) P a r t I of this series: D . Horton and M. L. Wolfrum, J . Orp. Chem.. 27, 1794 (1962); (b) Supported by contract no. DA-49-193-MD2143 (K.F. Proj. 1187) horn the Walter Reed Army Institute of Research, Washington, L).C . The orinions exjiressed in this article are those of the authors, and not necessarily those of the sponsoring agency. (2) I). H. Hiitson eratefiilly acknoxledaes a trayel yrant froru the Wellcollie T r u s t , 32 Queen Anne Ftreet. Londun, N ' 1.
(3) R. U. Lernieux, Aduan. Carhohydrate Chem., 9, 1 (1964); B. Capon and W. G . Overend, abid.. 15, 11 (1960). (4) .\. Hollaender. ed.. "Radiation Protection and Recovery," Pergamon Press, London, 1960. ( 6 ) J. X. Khyru, U. C . Dolierty. and R. Sliapira, J . A m . Chem. Soc.. 80,3342 ~19~x31.
